Hypotensive and renovascular actions of 6-keto-prostaglandin E1, a metabolite of prostacyclin

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Renin release induced by 6‐oxo‐prostaglandin E1 (6‐oxo‐PGE1) was compared to release in response to prostacyclin (PGI2) and 6‐oxo‐PGF1α in slices of rabbit renal cortex. Krebs‐Ringer medium bathing slices of renal cortex was collected for renin assay after four successive 20 min intervals (periods I‐IV). Renin release did not increase during periods I to IV in untreated slices. Agonists were added, only once, at the beginning of period III. Between periods III and IV, the incubation solution was aspirated and replaced with fresh medium. PGI2 increased renin release during period III while 6‐oxo‐PGE1 stimulated release during periods III and IV. 6‐oxo‐PGE1 stimulated renin release (24%–74%) in concentrations ranging from 1–33 μm while PGI2 stimulated release at 10 μm (60%) but not at 5 μm. 6‐oxo‐PGF1α, 10 μm, did not release renin during period III (period III, 9%), but caused a small rise in period IV (29%). 6‐oxo‐PGE1, unlike PGI2, was stable under the incubation conditions (pH 7.4, 37°C) as indicated by recovery of undiminished platelet anti‐aggregatory material after 20 min. In the rabbit kidney, activity of 9‐hydroxyprostaglandin dehydrogenase was greatest in the cortex and negligible in the papilla, corresponding to the zonal distribution of renin. The prominent and sustained in vitro renin releasing effect of 6‐oxo‐PGE1, as well as the cortical localization of enzyme activity capable of generating this stable prostacyclin metabolite, suggest that formation of 6‐oxo‐PGE1 may contribute to PGI2‐induced renin release and may explain the delayed stimulation caused by 6‐oxo‐PGF1α.

Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

STIMULATION OF RENIN RELEASE BY 6‐OXO‐PROSTAGLANDIN E₁ AND PROSTACYCLIN

McGiff

Spokas

Wong

1982

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“…6-keto PGE1 assayed on the rat stomach strip was substantially inactivated after 60 min incubation in guinea-pig and rabbit kidney supernatant whereas little or no breakdown occurred in rat kidney. These results are also of interest since other authors have failed to detect pulmonary metabolism of this prostaglandin in vivo (Quilley, Wong & McGiff, 1979;. Thus 6-keto PGE1 like PG12 may not be a substrate for the pulmonary uptake mechanism in vivo.…”

Section: Discussionmentioning

confidence: 72%

Formation of 6‐keto prostaglandin E₁ in mammalian kidneys

Griffiths

Moore

1983

The metabolism of prostacyclin (PG12) and 6-keto prostaglandin F1l1 (6-keto PGF1<,) was studied in cell-free homogenates of rat, rabbit and guinea-pig kidney.2 Rabbit kidney converted both PGI2 and 6-keto PGF1. to a stable metabolite with chromatographic and biological activity identical to that of authentic 6-keto PGE1. Activity was found in the kidney cortex but not medulla, was inhibited by NAD+ or NADP+ (5 mM) and showed an optimum temperature requirement of 37°C.3 Guinea-pig kidney converted PGI2 but not 6-keto PGF1C, to a labile, biologically active metabolite which was not 6-keto PGE1.4 No conversion of prostacyclin or 6-keto PGF1,, to biologically active metabolites occurred in cell-free homogenates of rat kidney, liver and colon or guinea-pig liver and colon. 5 6-keto PGE1 rapidly lost spasmogenic activity on the rat stomach strip following incubation with rabbit or guinea-pig kidney supernatant in the absence of added cofactors. No loss of activity occurred on incubation with rat kidney. 6 Rutin (50 riM) potently inhibited synthesis of 6-keto PGE1 from added PGO2 by rabbit kidney cortex. This reaction was potentiated by a similar concentration of sulphasalazine, carbenoxolone, imidazole, papaverine or indomethacin. 7 The relevance of these findings for the possible physiological and pathological roles of 6-keto

“…6-oxo-PGE, shares many similar pharmacological properties with prostacyclin, and is often equipotent or more potent (for reviews see Moore ; . For example, it is vasodilator and hypotensive (Quilley et al, 1979;Van Dam et al, 1981; Tod & Cassin, 1981), bronchodilator (Spannhake et al, C) The Macmillan Press Ltd 1986 1981), inhibits platelet aggregation (Wong et al, 1980b;Miller et al, 1980;Whittle et al, 1981;Berry & Hoult, 1983), and induces renal release of renin (Jackson et al, 1981;McGiff et al, 1982) and of erythropoietin (Nelson et al, 1983).…”

mentioning

confidence: 99%

Identification of 6‐oxo‐prostaglandin E₁ as a naturally occurring prostanoid generated by rat lung

Berry

Griffiths²,

Hoult

et al. 1986

1 The spontaneous release of prostanoids from rat isolated perfused lungs was studied after acid/ organic extraction of perfusates by bioassay, radioimmunoassay, thin layer and high performance liquid chromatographic methods and by gas chromatography-negative ion mass spectroscopy (g.c.-n.i.m.s.). 2 An acid/organic extractable anti-aggregatory vasodilator prostaglandin which inhibited the twitch response of the field-stimulated guinea-pig vas deferens was released from the Krebs-perfused rat lung in nanogram amounts similar to those of other detected prostanoids. Parallel biological assay suggested that this prostaglandin had very closely similar pharmacological activity to authentic 6-oxo-prostaglandin E, (6-oxo-PGE,), a metabolite ofprostacyclin (PGI2) generated by the action of the enzyme 9-hydroxyprostaglandin dehydrogenase (9-PGDH). 3 6-oxo-PGE, was identified conclusively in extracts of rat lung perfusate by thin layer chromatography, high performance liquid chromatography and g.c./m.s. combined with bioassay (inhibition of platelet aggregation), and its covalent structure was defined by g.c. negative ion chemical ionization mass spectroscopy. 4 The rank order of spontaneous release of prostanoids (measured by radioimmunoassay) from the perfused rat lung was 6-oxo-PGFI, > thromboxane B2 (TXB2) > PGE2 > 6-oxo-PGE1 (measured biologically) > PGF2,. Release of all five prostanoids was inhibited by indomethacin, but only that of 6-oxo-PGE, was inhibited by naringenin. 5Rat lung lOO,OOOg cytosolic supernatants contained 9-PGDH activity capable of removing 9p-tritium from labelled prostacyclin and forming an acid/organic extractable 6-oxo-PGEI-like antiaggregatory substance. This 9-PGDH activity was inhibited by naringenin (IC50 10.3 PM). 6 The relevance of these findings to the possible physiological role of 6-oxo-PGE1 in the lung is discussed, and we propose that 6-oxo-PGE, should be accorded the status ofa physiologically relevant, naturally occurring metabolite of arachidonic acid.